The management of premature labor is one of the most important issues in the field of obsterics. Premature labor refers to parturition on or after 22 weeks and before 37 weeks of pregnancy, which accounts for 5 to 10% of the total number of childbirths. A neonate delivered by premature labor is called a pronatus, which is frequently a low birth weight infant. Recently, although the care of neonates has progressed significantly, the morbidity and mortality of pronatuses are higher compared to normally delivered neonates. Therefore, it is desired that premature labor is avoided to continue pregnancy as long as possible.
At present, widely used drugs for preventing premature labor include β2-adrenergic sympathetic agonist, magnesium sulfate, and indomethacin (a prostaglandin synthesis inhibitor).
Ritodrine, which is a representative β2-adrenergic agonist, causes various cardiovascular and metabolic side effects, including tachycardia, elevation of renin secretion, and hyperglycemia in mothers (and hypoglycemia in neonates). Other β2-adrenergic agents, such as for example terbutaline and albuterol, cause side effects similar to those of ritodrine.
Magnesium sulfate having a plasma concentration of 4 to 8 mg/dL, which exceeds the therapeutically acceptable range, causes inhibition of cardiac conduction and neuromascular transmission, hypopnea, and cardiac arrest. Therefore, when renal function is impaired, this agent is not preferable.
Indomethacin causes side effects in fetuses, such as for example pulmonary artery hypertension and persistent truncus arteriosus, which are contraindications to large dosage and long-term use of indomethacin.
As described above, currently known drugs for preventing premature labor have various drawbacks. Therefore, there is a demand for a novel drug for preventing premature labor without such drawbacks.
The mechanism of the onset of parturition, i.e., the beginning of pains, has not been yet fully revealed, but it has been suggested that oxytocin, prostaglandin, and the like having a uterine contracting action are involved. Bradykinin has a uterine contracting action similar to oxytocin and prostaglandin, but the physiological or pathophysiological meaning is still unknown. However, bradykinin is inherently an inflammatory mediator, and it has been suggested that there is a possibility that premature labor and miscarriage is caused by abnormally increased bradykinin in the gravid uterus, (Reference 1; List of references are described at the end of this specification). Therefore, if a drug capable of inhibiting spontaneous myometrial contraction or bradykinin-induced myometrial contraction action, or a drug capable of selectively inhibiting spontaneous myometrial contraction or bradykinin-induced contraction action, was especially found, the drug would be expected to be useful not only for preventing premature labor but also for preventing miscarriage and arresting of parturition prior to cesarean section.
Further, such an agent would be expected to be useful in the treatment of dysmenorrhea. This is because dysmenorrhea is characterized by a periodic pain in association with menses during a ovulocycle, and the pain is believed to be derived from uterine contraction and ischemia.
Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, was originally isolated from human pheochromocytoma as a peptide having a hypotensive action (Reference 2). It is known that AM plays multiple roles in a variety of tissues (Reference 3). This suggests that AM has a nonuniform mechanism of action in an organism.
Levels of AM protein or AM mRNA in the female reproductive system (e.g., pituitary posterior lobe [Reference 3] and the uterus [Reference 4]), are as high as those in adrenal medulla. Also, level of circulating AM in maternal blood (Reference 5), and AM and AM mRNA abundance in fetal-placental tissues (Reference 6) and the uterus (Reference 7) were both elevated during normal pregnancy. In gestosis, a complication of pregnancy, the maternal plasma AM level did not alter (Reference 5), or lowered (Reference 8), whereas the AM content in amniotic fluid and umbilical vein were higher, compared to normal pregnancy (Reference 9). However, physiological roles of AM and details of AM function in these fetal and maternal tissues remain elusive.
As to the effect of AM on uterine contraction, it has only been reported that AM inhibited galanin-induced tonic contraction of the uterus at high concentrations of 5 μM or more, and the action of AM was eliminated by CGRP[8-37] (Reference 7). Galanin is a neuropeptide contained in a neuron (CGRP). However, the importance of galanin-induced uterine contraction is not understood at all. AM action is not found at concentrations of the order of nanomolar (nM) or less (which are the concentrations reported in a number of papers as concentrations at which AM can function). It has been only confirmed that AM can function at high concentrations of the order of micromolar (μM) or more. Therefore, it is hardly believed that these effects reflect a physiological function of AM.
The motility of the uterus (contraction/relaxation) is not only regulated by nerves, such as sympathetic nerves and parasympathetic nerves, but also is coordinately regulated by various substances, such as for example CGRP (Reference 10), nitric oxide (NO), oxytocin, and prostaglandin F2α (PGF2α: a representative prostaglandin having various actions: elevation of blood pressure; vasoconstriction; promotion of intestine movement; uterine contraction; promotion of regression of corpus luteum; and bronchoconstriction, and used as a parturifacient). Similar to bradykinin described above, substances which can cause abnormal contraction leading to premature labor also influence the motility of the uterus. However, what effect is obtained by AM on spontaneous uterine contraction; the contractility evoked by regulatory factors, such as oxytocin, PGF2α and the like; or bradykinin-induced contraction, is not known at all.
The present invention is intended to solve the above-described problems. The objective of the present invention is to provide a novel agent for inhibiting, preferably selectively inhibiting, spontaneous myometrial contraction or bradykinin-induced contraction.